Current update on the protective effect of epicatechin in neurodegenerative diseases

1 School of Pharmacy, Suresh Gyan Vihar University, Mahal Road, Jagatpura 302017, Jaipur, India 2 Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India 3 Uttaranchal Institute of Pharmaceutical Sciences, Uttaranchal University, Dehradun, India 4 Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia 5 Inva-Health Inc, Cranbury, NJ 08512, USA 6 School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab, 144411, India 7 Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia 8 Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia 9 Department of Pharmacology, Maharishi Arvind College of Pharmacy, Ambabari Circle, Ambabari, Jaipur, 302023, India

Neurodegenerative diseases are characterized by the progressive loss of neural structures instead of the selective neuronal loss caused by metabolic or toxic disorders. Alzheimer's, Parkinson's, Huntington's, and amyotrophic lateral sclerosis are among the several neurodegenerative diseases for which there is no treatment (Ruz et al., 2020). New and better treatment strategies are urgently required to tackle these fatal illnesses. For example, epicatechin is one of the most prevalent and plentiful flavonoids (Figure 1). Numerous organs and tissues, including the heart, skeletal muscle, and neurons, have been studied, and epicatechin has been associated with mitochondrial improvement (Panneerselvam et al., 2013). Epicatechin has been demonstrated to aid in treating neurodegenerative diseases, although there is little data to back this claim (Shaki et al., 2017). The discoveries will also offer researchers a roadmap for developing neuroprotective drugs that are safe and effective (Table 1).  Ali et al. looked at the role of EC, Vitamin E, Vitamin C, and Se in improving the potential impact of physical and mental activities (Ph&M) over socially isolated and protein malnourished (SI&PM) as risk factors for Alzheimer's disease development in rats. In the AD, SI&PM, and SI&PM/AD groups, the combination of EC, VE, VC, and Se with Ph&M boosted brain monoamines, SOD, TAC, and BDNF. In addition, SI&PM-induced AD risk was reduced when antioxidants were combined with Ph&M activities.

Ali et al., 2021
The impact of EC on the memory function of AD rats was studied by Nan et al. After the AD rats were given EC, they spent more time in the target quadrant, demonstrating that EC may reduce Tau hyperphosphorylation, downregulate BACE1 and Aβ1-42 expression, and boost AD rats' antioxidant system as well as their cognition and memory. Nan et al., 2021 Using isolated rat hippocampus mitochondria in vivo, Shaki et al. examined the effect of EC on mitochondrial damage produced by homocysteine (Hcy). EC decreased LPO and ROS levels while raising GSH levels concurrently. It has been shown that EC protects against oxidative stress, reduces mitochondrial damage, and cures neurological diseases caused by Hcy, including Alzheimer's disease.

Shaki et al., 2017
Diaz and colleagues investigated the effects of EC on Aβ25-35 neurotoxicity on spatial memory and the interaction between HSP immunoreactivity in the CA1 area of the rat HP. Treatment with EC reduces the risk of Alzheimer's disease. EC improves spatial memory performance by reducing A25-35-induced neurotoxicity, HSP-60, -70, and -90 immunoreactivity, and neuronal loss in the CA1 region of the Hp of A25-35-injected rats.

Diaz et al., 2019
Wang et al. studied that 3′-O-methyl-epicatechin-5-O-glucuronide was discovered for the first time in a biosynthetic EC metabolite and that proanthocyanidin (PAC) metabolites found in the brain monomeric (Mo) therapy increase baseline synaptic transmission in hippocampal slices via mechanisms associated with CREB signaling. Wang et al., 2012 N'Go et al. investigated whether natural components from Chrysophyllum perpulchrum, such as EC and two dimeric procyanidins (EC + hexose), potentially inhibit the development of oxidative stress and cognitive abnormalities in a rat model of AD generated by Aβ1-40 injection into the CA1 region of the hippocampi. A rat's identification memory and spatial learning were much weaker. This was linked to an increase in Iba 1 immunoreactivity and NO levels in microglia. In the hippocampus, prefrontal cortex, and septum of AD-like animal models, malondialdehyde and SOD levels were associated, but not thiol content.
N'Go et al., 2021 Ferruzzi et al. found that frequent exposure to Grape seed proanthocyanidin extract (GSPE) enhanced bioavailability.
In the brain tissues of rats given a single dose of GSPE, neither EC nor catechin (C) was found. Repeated delivery of GSPE seems to affect the accumulation of GA, C, and EC in the brain. Ferruzzi et al., 2009 Vinpocetine, alone or in combination with EC, CoQ10, or VE & Se, was investigated for its possible neuroprotective effect and mechanism of action in reducing aluminum chloride-induced AD in rats by Ali  Al-Amri and co-authors aimed to determine if EC might inhibit the production of inflammatory mediators and protect dopaminergic neurons from LPS-induced neurotoxicity. Antioxidant EC was shown to have a possible therapeutic effect against LPS-induced neurotoxicity by decreasing TNF-alpha and NO inflammatory mediators in the midbrain while preserving DA levels.
Al- Amri et al., 2013 According to a study by Li et al., both the human dopaminergic cell line SH-SY5Y and primary rat mesencephalic cultures were significantly protected against microglial activation-induced neuronal injury by EC. The results indicate that EC is a potent inhibitor of microglial activation, suggesting that it might be employed to treat microglia-mediated dopaminergic neuronal damage in Parkinson's disease. Li et al., 2004 The impact of EC on climbing ability, LPO, and apoptosis in the brains of PD model flies was explored by Siddique et al. The administration of 0.25, 0.50, and 1.0 g/mL of EC to the brains of PD model flies in a dose-dependent way; it reduced oxidative stress and apoptosis while preventing the loss of climbing ability.

Siddique et al., 2014
Huntington's Disease Kumar and Kumar (2009) demonstrated the effects of lycopene and EC on memory impairment and how 3-NP therapy disrupts the glutathione system. Treatments with lycopene and EC restored glutathione system function and dramatically enhanced memory. Kumar and Kumar, 2009 The green tea polyphenol EC prevents mutant htt exon 1 protein from aggregating in a dose-dependent way. In vitro, EC contains mutant htt exon 1 protein from misfolding and oligomerizing, indicating that it interferes with early aggregation processes. According to their findings, EC, a modulator of htt exon 1 misfolding and oligomerization, may be able to attenuate polyQ-mediated toxicity in vivo. Ehrnhoefer et al., 2006 The concept, that the presence of lipid vesicles affected the function of EC, was examined by Beasley et al. Curcumin was prevented from suppressing the formation of htt fibrils by adding 1-palmitoyl-2-oleoyl-glycerol-3-phosphocholine or vesicles generated from a whole-brain lipid extract. These findings suggest that EC and other htt exon 1 misfolding and oligomerization modulators might lower polyQ-mediated toxicity in vivo.

Beasley et al., 2019
Cano et al. claim that ascorbic acid was used to integrate EC into PEGylated poly(lactic-co-glycolic acid) NPs. Intoxication with 3-nitropropionic acid caused HD-like striatal lesions and motor deficits in mice. Motor abnormalities and depressive-like behavior related to 3-nitropropionic acid poisoning were considerably reduced by EC/AA NPs than by free EC. Treatment with EC/AA NPs also reduced neuroinflammation and stopped neuronal loss. Cano et al., 2021 According to AvramovichTirosh et al., M-30 and EC reduced apoptosis in human SH-SY5Y neuroblastoma cells in a neurorescue, serum deprivation model via multiple protection mechanisms. These mechanisms included the reduction of pro-apoptotic proteins and the promotion of Avramovich-Tirosh et al., 2007 morphological changes. In addition, these changes resulted in axonal growth-associated protein-43 (GAP-43), which was implicated in neuronal differentiation. Lewy Body Disease Iron is essential for the pathophysiology of oxidative stress, which involves the death of dopaminergic neurons and the degradation of proteins via ubiquitination, highlighting the relevance of iron in these processes. In rats and non-human primates, iron and -synuclein accumulation in the SNpc is linked to MPTP-induced neurodegeneration. In MPTP-induced dementia, the iron buildup has been connected to the ubiquitination of iron regulatory proteins, related to NO-dependent mechanisms. The buildup of iron and -synuclein in the SNpc of mice and rats is inhibited by EC and other radical scavengers. These radical scavengers protect the nervous system against neurotoxins.

Mandel et al., 2004
Amyotrophic Lateral Sclerosis (ALS) In a transgenic mouse model of ALS, Xu and colleagues investigated the neuroprotective effects of EC. SOD1-G93A transgenic mice and wild-type mice were separated into EC-treated and vehicle-treated control groups at random intervals. Oral EC treatment started at a pre-symptomatic stage in a mouse model of ALS dramatically delayed illness onset and increased life duration. This research adds to the expanding amount of data that EC has various medicinal properties. Xu et al., 2006 According to Koh and colleagues, the impact of EC on ALS model mice with the human G93A mutant Cu/Zn-SOD1 gene, more than 2.9 micrograms of EC per gram of body weight prolonged symptom onset and duration of life, preserved more survival signals, and reduced death signals. These findings suggest that EC might be a disease-modifying treatment for persons with ALS. Koh et al., 2006